Risk for development of diseases and conditions like atherosclerosis, coronary artery disease, and coronary heart disease have been shown to be strongly correlated with certain plasma lipid levels. While elevated levels of low density lipoprotein-cholesterol (LDL-cholesterol) may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to e.g. coronary heart disease. Low levels of high density lipoprotein-cholesterol (HDL-cholesterol) is also a known risk factor for coronary heart disease (Gordon, D. J., et al., “High-density Lipoprotein Cholesterol and Cardiovascular Disease”, Circulation, (1989), 79: 8-15).
The risk for developing e.g. cardiovascular diseases is positively correlated with high levels of LDL-cholesterol and triglycerides, while high levels of HDL-cholesterol are negatively correlated. More specifically, in the range from 0.5 mmol/l to 3 mmol/l an increase in the HDL-cholesterol level minimizes the risk for developing e.g. cardiovascular diseases.
Thus, dyslipidemia is not a unitary risk profile for diseases like coronary heart disease but may be comprised of one or more lipid aberrations.
Atherosclerosis and its associated coronary artery disease is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of dyslipidemia with dietary modification and drug therapy, coronary heart disease remains the most common cause of death in the U.S., where cardiovascular disease accounts for 44% of all deaths, with 53% of these associated with atherosclerotic coronary heart disease.
It has recently been investigated to what extent high and low levels of LDL- and HDL-cholesterol are indicative for the occurrence of major cardiovascular events. The study evaluated the effect of HDL-cholesterol levels in patients with clinically evident coronary heart disease who received statin therapy to reduce LDL-cholesterol levels. It was found that HDL cholesterol levels were predictive of major cardiovascular events in patients treated with statins, however, this relationship was also observed among patients with LDL-cholesterol levels below 70 mg/dL (see Philip Barter et al: “HDL Cholesterol, Very low levels of LDL Cholesterol, and Cardiovascular events”; N. Engl. J. Med., 2007, 357, (13), 1301-10). Although statin treatment provides an overall improvement in outcomes, clinical trial data reveal a significant number of cardiac events despite reaching targeted LDL levels. Accordingly, to reduce the risk of cardiovascular events it is not enough merely to lower the level of LDL-cholesterol but is can also be recommended to increase the level of HDL-cholesterol.
For instance a HDL-cholesterol level of less than 35 mg/dl (1.0 mmol/l) for men and less than 42 mg/dl (1.20 mmol/l) for women is a maker for an increased risk of e.g. cardiovascular diseases (see: Prevention of cardiovascular diseases in clinical practice. Guidelines of the third joint task force of European and other societies on cardiovascular disease prevention in clinical practice. European Heart Journal 2003; 24:1601-1610).
The American Heart Association recommends a plasma HDL-cholesterol level for adult men and women with an increased risk of cardiovascular diseases of above 40 mg/dl (1.18 mmol/l) and above 50 mg/dl (1.29 mmol/l), respectively. (L. Mosca, L. J. Appel, E. J. Benjamin et al. and American Heart Association, Evidence-based guidelines for cardiovascular disease prevention in women, Circulation; 109 (2004) (5), 672-693).
An analysis of data from four large studies has also previously been published, showing that each increase of 1 mg/dl (0.03 mmol/l) in HDL-cholesterol is associated with a decrease of 2 to 3% in the risk of future coronary heart disease. (Gordon et al. High-density lipoprotein and cardiovascular disease. Four prospective American studies. Circulation 1989; 79:8-15.)
Recently, a phase 3 clinical trial with a cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, was terminated because of increased mortality in the active treatment group (see Barter, P J, et al.; ILLUMINATE Investigators, Effects of torcetrapib in patients at high risk for coronary events, N Engl J Med 2007, 22; 357(21):2109-22). Accordingly, the previously believed theory that CETP inhibition could raise the HDL-cholesterol level suffered a blow. (See Rader, D. J.; Illuminating HDL—Is it still a viable therapeutic target?; N. Engl. J. Med.; 2007; 357; 21, p. 2180-2183).
No wholly satisfactory HDL-elevating therapies exist. Statins that are now widely used to lower LDL cholesterol levels in people with—or at risk of acquiring—cardiovascular disease, lower cholesterol by inhibiting the enzyme HMG-CoA reductase. Hereby is obtained an increased clearance of LDL from the bloodstream and a decrease in the blood cholesterol level. However, the administration of statins can be associated with safety issues such as e.g. serious but uncommon musculoskeletal reactions like rhabdomyolysis. Niacin can significantly increase HDL, but has serious toleration issues which reduce compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL-cholesterol only modestly (˜10-12%). As a result, there is a significant unmet medical need for a well-tolerated agent which can significantly elevate plasma HDL levels, thereby reversing or slowing the progression of diseases like atherosclerosis.